Optical isomers of acyl-beta-alkyl choline salts and intermediates and processes for their production



Patented May 24, 1938 UNITED STATES OPTICAL ISOMER-S OF ACYL-B-ALKYLCHO- LINE SALTS AND INTERBIEDIATES AND PROCESSES FOR THEIR PRODUCTIONRandolph T. Major, Plainfield, and Howard T. Bonnett, Rahway, N. J.,assignors to Merck & Co. Inc., Rahway, N. J., a corporation of NewJersey No Drawing. Application July 6, 1935, Serial No. 30,150

7 Claims.

This invention relates broadly to processes for preparingacyl-p-alkyl-choline iodides and salts of acids whose silver salts aremore soluble than silver iodide (specifically exemplified by processesfor the production of acetyl-fi-methyl-choline chloride), and relatingmore particularly to opti cal isomers thereof and methods for theirpreparation.

The co-pending application of one of us, Randolph T. Major, inassociation with Joseph K. Cline, Serial No. 733,604, filed July 3,1934, relates to the preparation of the racemic form of acetylti-methylcholine chloride.

Theoretically, it should be possible to prepare two optically activeforms of this and related choline compounds when they contain anasymmetric carbon atom. Since it is generally recognized that one of theoptical isomers of a medicinal chemical is usually much more activephysiologically than the other, it was considered desirable to attemptthe production of the theoretically possible optical isomers.

Pharmacological tests with the optical isomers of acetyl-B-methylcholine chloride show that the physiological action of the dform isstronger than even the racemic form; whereas the laevo form isconsiderably milder. Thus the production and isolation of both forms,together with the known racemic form, afford to the medical profession amuch wider range for accurate dosage and control with these highlypotent drugs.

The results of our experiments indicate that the most satisfactorymethod of producing these isomers, is to prepare them from thecorresponda ing optical isomers obtained by resolving the racemicdimethylaminoisopropanol by appropriate means, as will further appear,into its dand Z-forms, and to convert them, respectively, into theircorresponding methyl choline iodides. Thereafter, we may prepare thechlorides or other salts from the iodides and then acetylate therespective compounds, as may be required. Proceeding in this manner, theoptical isomers of acetyl-B-methyl choline chloride are obtained aswhite crystalline hygroscopic solids; the dform having a melting pointof 200-201 C. and an optical rotation,

(a +41.9 and the l-form a melting point of 201-202 C. and a rotation,

(a)f, 41.3 Equal quantities of the dand l-forms showed a mixed meltingpoint of 172173 0., which corresponds to the melting point establishedby Major and Cline for the racemic form, i. e., 172-173 C.

The process as above described may also be applied to the production ofother salts- Obviously, such other salts of acids may be thus preparedwhere the acid involved is one whose silver salts are more soluble thansilver iodide.

The following description of the more detailed steps of the processexemplifies the general method as directed more particularly to theultimate production of both optical isomers of acetyl cmethyl cholinechloride.

Resolution of dimethylaminoisopropanol Dimethylaminoisopropanol, isknown to be racemic and its resolution into the dand Z-forms isaccomplished by us in the following manner:

d-form.-Dimethylaminoisopropanol, having a boiling point of 124-126 0.,is treated with 5% excess bromo-camphorsulfonic acid in ethyl acetatesolution. The salt is recrystallized from a mixture of 5 cc. ethylacetate and 1 cc. absolute alcohol per gram of salt, its rotationbecoming constant at +835". The dextro-amine is obtained from the saltby treating the latter with an excess of NaOH, extracting with ether,drying the ether solution with anhydrous K2CO3, and distilling atatmospheric pressure. It has a. boiling point of l24.5-l26.0 C. 770 mm.;optical rotation,

l-form.Dimethylaminoiscpiiopanol having a boiling point of l24-126 C.,is treated with 1.05 mols of d-tartaric acid in alcohol solution. Thesalt is recrystallized from a mixture of 6 cc.

96% alcohol per gram of salt. After repeated recrystallizationa'a saltis obtained having rotation,

(11%; 10.7 The laevo-amine is obtained frorn'the salt by treating thesame with an excess of NaOH, extracting with ether, drying the ethersolution with anhydrous KzCOa, and distilling at atmospheric pressure.It has a boiling point of and optical rotation, about 0% 15 The racemicamine may also be resolved into its dand Z-forms by treating it withbromocamphorsulphonic acid to separate out the dextro-form, removing thebromo-camphorsulphonic acid from the salt, and treating the residue ofthe amine thus liberated with d-tartaric acid to obtain the laevo 'formafter-further purification.

The reverse of the process may also be followed by first treating theracemic taric acid to resolve the laevo-form, removing the d-tartaricacid, and treating the residue of the amine with bromo-camphorsulfonicacid to obtain the dextro-form, all substantially in the mannerdescribed. I

Preparation of dand Z-e-methylcholine iodides the l-s-methylcholineiodide has a melting point of 176.5-177.5C., and,

(a), =-24.7 Preparation of dand l-fl methylcholine chlorides The dandl-p-methylcholine chlorides are prepared by reacting upon the respectiveiodides with AgCl in alcohol solution. The silver salts' formed in thereaction are removed by filtration.

. The last traces of silver chloride are removed by passing hydrogensulfide into the solution. Char- 'coal'is added and the mixturefiltered. The filtrate is concentrated to argummy consistency, and thenthe salts are recrystallized'from butyl alcohol. The d-B-methylcholinechloride "has a melting point of 165-167" C., and

, 0% +381;0 the laevo-form, a melting point of 165- 167", and

(00%; 382 Preparation of dand'l-s-methylcholine salts In general,various salts of dand l-p-methylcholine may be prepared by reacting uponthe inethiodides of the respective isomers with the corresponding silversalt of an acid whose silver salt is more soluble than silver iodide.

Preparation of acetyl dand Z-amethylcholine chloride choline chloridewith seven molecular portions of acetic anhydride is heated for three tosix hours at 100 C. Dry ether is then added to the cooled solution. Theprecipitate which forms is washed several times with ether and thendissolved in absolute alcohol. This solution is first decolorized withactivated charcoal, and then the acetylated compound reprecipitated bythe addition of dry ether. The products obtained are white crystallinehygroscopic solids. The dextro form has a melting point of 200-201";

The laevo-form has a melting point of 201-202" 0.;

A mixture of equal quantities of the dand Z- forms gives a mixed meltingpoint of 172 17}? C.

1 pThe racemic forms of all the intermediate and ultimate products arereadily produced by the same zite'ps throughout without resolving theracemic dimethylaminoisopropanol into its opti cal isomers, thus:

Racemic dimethylaminoisopropanol methyl iodide B-methyl-choline iodideSilver salt ,8-methyl-choline salt acylating agent Racemicacyl-[3-methyl-chollne salt.

It will be apparent that various modifications may be made in any of thesteps in the processes as described without departing from the spiritand scope of the invention. 7

We claim as our invention:-

l. The process of producing optically active isomers of acyl-B-methylcholine salts, which comprises the steps of resolvingdimethylaminoisopropanol into its dextro and laevo forms by treating theracemic form of the amine, with an acid of the group consisting ofbromo-camphorsulphonic acid and d-tartaric acid, subsequently treatingthe resolved forms thus obtained with methyl iodide to form theirmethiodides, and

thereafter converting the methiodides into the desired salts by reactingupon them with the a silver salt of a corresponding' acid whose silversalt is more soluble than silver iodide, and acylating the salt thusobtained. V, r

2. Acetyl d-e-methylcholine chloride being in .the form of a whitehygroscopic crystalline solid, having, in its pure form a melting pointof about ZOO-201 C., and optical rotation about 3. Acetyll-c-methylcholine chloride being in the form of a white hygroscopiccrystalline solid, having, in its pure form a melting point of about201-202 C. and optical rotation about e. The process of producingacyl-fi-methylcholine salts which comprises the steps of treatingdimethylaminoisopropanol with methyl iodide to form its methiodide, andthereafter converting the methiodides into the desired salts by reactingupon them with the silver salt of a corresponding acid whose silver saltvis more soluble than silver iodide, and acylating the salt thusobtained.

5. Optically active acetyl-B-methylcholine salts of acids whose silversalts are more soluble than silver iodide.

6. Theprocess of producing d-acyl-B-methyl choline salts which comprisesthe steps of re solving dimethylaminoisopropanol into its dextro form bytreating the racemic form. of the amine with bromocamphorsulfonic acid,subsequently treating the dextro form thus obtained with methyl iodideto form its methiodide, thereafter converting the methiodide into thedesired salt by reacting upon it with the silver salt of an acid whosesilver salt is more soluble than silver iodide, and acylating the saltthus obtained. 7

7. The process of producing i-acyl-B-m'ethyl choline salts whichcomprises the steps of resolving dimethylaminoisopropanol into its laevoform by treating the racemic form of the amine with d-tartaric acid,subsequently treating the laevo form thus obtained withmethyl iodide toform its methiodide, thereafter converting the methiodide into thedesired salt by reacting upon it with the silver salt of an acid whosesilver salt ismore soluble than silver iodide, and acylating the salt'HOWARD T. BONNETT. V 7

